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Chapter 1Introduction

Perspectives: Why Guidelines Differ

Alan J. Magill, David R. Shlim

INTRODUCTION

Numerous international, national, and professional organizations publish guidelines and recommendations that assist travel health providers in giving the best possible advice to prospective travelers. The CDC Yellow Book is one example of published recommendations. However, it is quickly apparent to both clinicians and patients that guidelines and recommendations differ, sometimes dramatically. Conflicting messages from authoritative sources may confuse patients and clinicians, and undermine the credibility of the source. It can be unsettling for patients to receive travel medicine advice, vaccines, and an antimalarial drug prescription from a provider, only to find that the recommendations conflict with what they have obtained from other sources, or even heard from other advisors. The skillful travel health provider will be able to help the traveler run this gauntlet of conflicting advice by knowing more about why guidelines differ.

HOW ARE GUIDELINES CREATED?

Most guidelines of interest to travel health providers and travelers focus on recommendations for immunizations, prophylactic medications, and self-treatment regimens (such as those for travelers’ diarrhea). Guidelines come from many sources. A regulatory agency in each country must review and approve an application from the sponsor of a product in order for the product to be commercially distributed. Regulatory authorities review data from prelicensure clinical trials and also assess the manufacturing process. International organizations such as the World Health Organization (WHO) promote their own sets of guidelines. At national levels, agencies such as CDC make recommendations for the use of approved vaccines and medications for travelers. In addition, professional organizations may create consensus clinical practice guidelines based on published medical literature and expert opinion. Travel medicine–specific subscription services use experts to organize and present travel medicine recommendations for clinicians. However, these services can use information and sources that may not be fully validated by national and international authorities. Finally, vast quantities of unregulated opinions are published on the Internet. People new to travel medicine may not be aware of the decision-making process or the source information that results in formal recommendations from these organizations.

Regulatory Authorities

Countries typically have a national regulatory authority which acts as the government body that approves vaccines and drugs. In the United States, this is the Food and Drug Administration (FDA). For the vaccines and medications commonly prescribed in a pre-travel consultation, providers are expected to use the products in accordance with the product label as approved by the FDA. The product label is a valuable source of information that is accurate at the time it is published. Manufacturers submit a detailed application that undergoes rigorous, multidisciplinary review. The approved product label reflects the information provided by the manufacturer in response to the requirements specified by a large body of regulatory law developed over many years. Since each country has different laws and requirements, approved products and their product labels may differ from country to country. This difference is then reflected in the national guidelines that relate to that product.

International Organizations

Travelers’ health information is provided by WHO’s publication, International Travel and Health (the “Green Book”) and also in the WHO International Health Regulations 2005. Countries with less-developed or nonexistent regulatory agencies often default to the WHO guidelines, while more-developed countries with resources devoted to travelers’ health may be aware of the WHO recommendations, but may not be able to reconcile WHO recommendations with their own country’s recommendations in every situation.

US National Organizations

CDC provides recommendations for travel health and publishes those recommendations in this book. Subject-matter experts at CDC review information in their area of expertise and formulate recommendations. For vaccines, the Advisory Committee on Immunization Practices (ACIP) develops written recommendations for the administration of vaccines, including travelers’ vaccines, to children and adults in the civilian population. Recommendations include age for vaccine administration, number of doses and dosing interval, and precautions and contraindications. ACIP, which is the only entity appointed by the federal government to make such recommendations, consists of 15 experts in fields associated with immunization who have been selected to provide advice and guidance to the US Department of Health and Human Services and CDC on the control of vaccine-preventable diseases (see Box 2-01).

Professional Organizations

Professional organizations often develop, write, and publish practice guidelines using committees of experts from their membership. These practice guidelines typically follow an evidence-based medicine approach that links recommendations to the strength and quality of the evidence as assessed by the committee members. The Infectious Disease Society of America has published a travel medicine practice guideline that many find useful. Practice guidelines, by their nature, are consensus documents.

Peer-Reviewed Medical Literature and Open Sources

As experience with a vaccine or a drug is acquired over the years, these results are often published in the peer-reviewed medical literature. In addition, people who use these products gain experience over time and develop their own opinions (“experience-based medicine”). The data that would be most useful in deciding how to use a vaccine or medication may not be available in published reports, so expert opinion attempts to interpret available information or provide background perspective.

WHY DO GUIDELINES DIFFER?

Guidelines in different countries and organizations may differ in substantial ways. Some of the reasons why guidelines differ include availability of products in different countries, a different cultural perception of risk, lack of evidence (or differing interpretations of the same evidence), and sometimes just honest differences in opinion among experts. Occasionally, public opinion may influence recommendations (for example, the widespread adverse publicity about mefloquine that was reported in the media).

Availability of Products

Travel health providers can only use the products that are available to them. Availability is determined by the regulatory approval status of the product and, to a lesser extent, the marketing and distribution plan of the manufacturer. Among the various vaccines and antimalarial drugs commercially available worldwide, the process for regulatory approvals varies greatly. For example, registering a new vaccine or antimalarial drug in the United States is a costly and rigorous process. If the market is insufficient to justify the expense of registration, then a commercial company may not seek registration in a particular country. The standards for licensure vary, and what may be sufficient for one regulatory authority may not suffice for another. For example, primaquine, an option for malaria chemoprophylaxis in the United States, is not registered or commercially available in Switzerland. Atovaquone-proguanil was available for malaria chemoprophylaxis in the United States before many other countries. On the other hand, an oral vaccine against cholera is approved for use and widely available in many countries, but is not approved by the FDA. Therefore, CDC and ACIP guidelines do not include any recommendations for the use of this vaccine.

Even when the same products are available, the recommendations for their use may differ. The capsular polysaccharide typhoid vaccine and the oral typhoid vaccine are examples. In the United States, a booster of the polysaccharide vaccine is recommended after 2 years, but in most European countries, a booster is recommended after 3 years. In the United States, a packet of 4 oral typhoid capsules is dispensed, whereas in Europe, 3 doses are considered adequate. The regulatory agencies may have reviewed the same data and drawn different conclusions, or they may have reviewed different data at separate times and reached different conclusions. Regulatory submissions to various agencies rarely are ready and occur at the same time; therefore, the data available for review by each agency may not be the same, for legitimate reasons.

Perception of Risk

People from varying backgrounds can view the same risk data and come to different conclusions as to the cost and benefit of preventing that risk. For example, national-level recommendations to prevent malaria while traveling to India vary widely. Germany does not recommend using standard prophylaxis for any travel to an Indian destination; standby emergency treatment (SBET or self-treatment) is the recommendation for identified risk destinations. The guidelines in the United Kingdom recommend only awareness and mosquito bite prevention for more than half the Indian subcontinent, including large cities and popular tourist destinations in the north and south, while recommending an individual risk assessment that is based on activities and types of travelers. Standard prophylaxis recommended in the UK guidelines is the combination of chloroquine plus proguanil (an option not available in the United States) for much of the middle of the subcontinent. However, CDC recommends malaria chemoprophylaxis for any Indian destination except for some mountainous areas of northern states above 2,000 m (6,561 ft). Is one of these guidelines better than the others? Not necessarily, as the recommendations may be based on the national experience with different types of travelers and the risk assessment approach of the organization formulating the national guidelines. For example, in 2010, CDC reported 216 malaria cases acquired in India by returning US travelers, the second highest absolute number of cases from any destination. However, when viewed as estimated relative case rates (the number of cases among US travelers attributable to each country divided by the estimated travel volume for US travelers to that country), countries in sub-Saharan Africa remain well above the median estimated risk, and India falls below the median estimated risk because of the much higher volume of travel to India. India reports active transmission in all provinces in the country. Based on the extremely large population of India, some of these provinces have high absolute numbers of cases but low case rates. Some countries base their recommendations on these relatively low case rates, but other countries believe that the high absolute numbers of cases result in large numbers of infective mosquitoes that can, in turn, infect travelers. In any case, travelers to India are likely to encounter diverse recommendations for malaria prevention on the Internet or from other travelers.

The best available data should always balance the risk of the intervention— and the costs—against the risk of the disease, so that the decision to recommend a vaccine or prophylactic medicine may be understood by the clinician and the traveler.

Lack of Evidence

In many cases, limited or no data are available to inform an evidence-based assessment. In this setting, travel health providers defer to expert opinion or an extrapolation from limited data in conjunction with expert opinion. In travel medicine, it is rare to have actual prospective numerator and denominator data on the risk of any vaccine-preventable diseases in travelers. For example, any data on the risk of hepatitis A in travelers would have to account for the immunization rate with hepatitis A vaccine. These data are rarely available, and therefore, we often rely on historical data that captured few actual cases.

CAN WE HARMONIZE GUIDELINES?

The complex nature of how we obtain, evaluate, and verify data, combined with the fundamental differences in risk perception, makes it likely that multiple, overlapping, and at times conflicting guidelines will continue to exist. However, given the international nature of travel medicine and the existence of the International Society of Travel Medicine, conflicting guidelines have decreased in the past decade. In one example of an effort to harmonize guidelines, from 2008 through 2010, WHO convened an international group of yellow fever and travel medicine experts to review available data on yellow fever virus transmission. The product of this collaboration was a country-specific list of yellow fever vaccine recommendations based on the geographic distribution of risk (see Chapter 3, Travel Vaccines & Malaria Information, by Country).

In summary, the role of the travel health provider is to become more sophisticated in his or her understanding of the various differences in guidelines, in interpreting this information, and in conveying it in an assured and comforting manner to travelers.

Committee to Advise on Tropical Medicine and Travel. Canadian recommendations for the prevention and treatment of malaria among international travellers—2009. Can Commun Dis Rep. 2009 Jul;35 Suppl 1:1–82.